One goal of the Section on Drosophila Gene Regulation is to understand the regulation of homeotic gene function in Drosophila. The homeotic genes encode homeodomain-containing transcription factors that control cell fates by regulating the transcription of downstream target genes. The homeotic genes are expressed in precise spatial patterns that are crucial for the proper determination of segmental identities.[unreadable] Cis-acting transcriptional regulatory elements from the homeotic genes have been previously-identified by assays in transgenes in Drosophila. These assays have identified both tissue-specific enhancer elements, as well as cis-regulatory elements that are required for the maintenance of activation or repression throughout development. While these transgene assays have been important in defining the structure of the cis-regulatory elements and identifying trans-acting factors that bind them, their functions within the contexts of the endogenous genes is still not well understood. We have used a large number of existing chromosomal rearrangements in the Sex combs reduced homeotic gene to investigate the functions of the cis-acting elements within the endogenous gene. Characterization of the chromosomal rearrangements revealed that two genetic elements about 70 kb apart in the Sex combs reduced gene must be in cis to maintain proper repression. When not physically linked to each other, these elements interact with elements on the homologous chromosome and cause derepression of its wild-type Sex combs reduced gene. Using a transgene assay, we have identified candidate fragments of DNA that may correspond to these regulatory elements. We are deleting these elements from the endogenous Sex combs reduced gene by targetted gene replacement. Genetic studies identified the trithorax group of genes that are required for expression or function of the homeotic genes. One of the first trithorax group genes identified is the female-sterile-homeotic gene. We have shown that one of the protein isoforms encoded by the female-sterile-homeotic gene interacts with DNA sequences just upstream of the promoter of the Ultrabithorax homeotic gene. This interaction makes the Ultrabithorax promoter responsive to regulation by distant cis-regulatory elements.